title: Extrathymic induction of Foxp3⁺ regulatory T cells declines with age in a T-cell intrinsic manner.
abstract: Extrathymically induced Foxp3⁺ regulatory T (Treg) cells contribute to the pool of Treg cells and are implicated in the maintenance of immune tolerance at environmental interfaces. The impact of T-cell senescence on their generation and function is, however, poorly characterized. We report here that steady-state induction of Foxp3 is impaired in aged T cells in vivo. In vitro assays further revealed that this defective generation of Treg cells was independent from the strength of TCR stimulation and arose before T-cell proliferation. Importantly, they also revealed that this impairment of Foxp3 induction is unrelated to known age-related T-cell defects, such as IL-2 secretion impairment, accumulation of activated T-cell populations, or narrowing of the T-cell repertoire. Finally, a loss of extrathymic induction of Foxp3 and tolerance to minor-mismatched skin graft were observed in aged mice treated by nondepleting anti-CD4 antibody. The T-cell intrinsic impairment of Treg-cell generation revealed here highlights age as a key factor to be considered in immune tolerance induction.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U1013, Université Paris Descartes, Sorbonne Paris Cité, Faculté de médecine, Paris, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Carpentier
authors.forename: Pascal
authors.initials: P
authors.lastname: Chappert
authors.forename: Chantal
authors.initials: C
authors.lastname: Kuhn
authors.forename: Mélanie
authors.initials: M
authors.lastname: Lalfer
authors.forename: Héloïse
authors.initials: H
authors.lastname: Flament
authors.forename: Odile
authors.initials: O
authors.lastname: Burlen-Defranoux
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantz
authors.forename: Antonio
authors.initials: A
authors.lastname: Bandeira
authors.forename: Bernard
authors.initials: B
authors.lastname: Malissen
authors.forename: Jean
authors.initials: J
authors.lastname: Davoust
authors.forename: David-Alexandre
authors.initials: DA
authors.lastname: Gross
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D015704:CD4 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D015778:Minor Histocompatibility Antigens / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016038:Skin Transplantation; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015778:Minor Histocompatibility Antigens; D011948:Receptors, Antigen, T-Cell
keywords: Aging; Foxp3; Regulatory T (Treg) cells; Transplantation